Substituted pyrazolo [1,5-A] pyrimidine compounds as TRK kinase inhibitors

Abstract

Compounds of Formula I: and salts thereof in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification, are inhibitors of Trk kinases and are useful in the treatment of diseases which can be treated with a Trk kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

What is claimed is: 
     
       1. A method for treating one or more symptoms of a cancer exhibiting one or more of overexpression, activation, amplification, and mutation of a Trk kinase in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is H or (1-6C alkyl); 
 R 2  is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl, -(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl, -(2-6C)chlorofluoroalkyl, -(2-6C)difluorochloroalkyl, -(2-6C)chlorohydroxyalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , -(1-6C alkyl)NHSO 2 (1-3C alkyl), -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl) 2 , -(1-6C alkyl)NHC(═O)O(1-4C alkyl), -(1-6C alkyl)hetCyc 1 , -(1-6C alkyl)hetAr 1 , hetAr 2 , hetCyc 2 , —O (1-6C alkyl) which is optionally substituted with halogen, OH or (1-4C)alkoxy, —O(3-6C cycloalkyl), Cyc 1 , -(1-6C alkyl)(3-6C cycloalkyl), -(1-6Calkyl)(1-4C alkoxy), -(1-6C hydroxyalkyl)(1-4C alkoxy), a bridged 7-membered cycloalkyl ring optionally substituted with (1-6C)hydroxyalkyl, or a bridged 7-8 membered heterocyclic ring having 1-2 ring nitrogen atoms; 
 or NR 1 R 2  forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-6C)alkyl, OH, CO 2 H, (1-3C alkyl)CO 2 H, —O(1-6C alkyl) and (1-6C)hydroxyalkyl; 
 hetCyc 1  is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 1  is optionally substituted with oxo, OH, halogen or (1-6C)alkyl; 
 hetCyc 2  is a 6 membered carbon-linked heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 2  is optionally substituted with F, SO 2 NH 2 , SO 2 (1-3C alkyl) or halogen; 
 hetAr 1  is a 5-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-4C)alkyl; 
 hetAr 2  is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C)alkyl, (3-6C)cycloalkyl, halogen and OH; 
 Cyc 1  is a 3-6 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO 2 H, -(1-4C alkyl)OH, halogen and CF 3 ; 
 Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, —CF 3 —CHF 2 , —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl), (1-4C)alkyl and NH 2 , or (iii) a pyrid-2-on-3-yl ring optionally substituted with one or more substituents independently selected from halogen and (1-4C)alkyl; 
 hetCyc 3  is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with (1-6C)alkyl; 
 X is —CH 2 —, —CH 2 CH 2 —, —CH 2 O— or —CH 2 NR d —; 
 R d  is H or -(1-4C alkyl); 
 R 3  is H or -(1-4C alkyl); 
 each R 4  is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, —NH 2 , —NH(1-4C alkyl) and —CH 2 OH; and 
 n is 0, 1, 2, 3, 4, 5 or 6; 
 wherein said cancer is selected from the group consisting of neuroblastoma, ovarian cancer, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, bladder cancer, uterine cancer, rectal cancer, thyroid cancer, and kidney cancer. 
 
     
     
       2. The method of  claim 1 , wherein:
 R 1  is H or -(1-6C alkyl); 
 R 2  is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , -(1-6C alkyl)NHSO 2 (1-3C alkyl), -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl) 2 , -(1-6C alkyl)hetCyc 1 , -(1-6C alkyl)hetAr 1 , hetAr 2 , hetCyc 2 , —O(1-6C alkyl), —O(3-6C cycloalkyl), Cyc 1 , or a bridged 7-membered cycloalkyl ring, 
 or NR 1 R 2  forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from -(1-6C)alkyl, —OH, —CO 2 H and -(1-3C alkyl)CO 2 H; 
 hetCyc 1  is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 1  is optionally substituted with oxo; 
 hetCyc 2  is a 6 membered carbon-linked heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 2  is optionally substituted with F, SO 2 NH 2 , or SO 2 (1-3C alkyl); 
 hetAr 1  is a 5-membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with -(1-4C)alkyl; 
 hetAr 2  is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms and optionally substituted with one or more substituents independently selected from -(1-4C)alkyl; 
 Cyc 1  is 3-6 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO 2 H and -(1-4C alkyl)OH; 
 Y is (i) phenyl optionally substituted with one or more substituents independently selected from halogen, -(1-4C)alkoxy, —CF 3 —CHF 2 , —O(1-4C alkyl)hetCyc 3  and —O(1-4C alkyl)O(1-3C alkyl), or (ii) a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl) and (1-4C)alkyl; 
 hetCyc 3  is a 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; 
 X is —CH 2 —, —CH 2 CH 2 —, —CH 2 O— or —CH 2 NR d —; 
 R d  is H or -(1-4C alkyl); 
 R 3  is H or -(1-4C alkyl); 
 each R 4  is independently selected from halogen, -(1-4C)alkyl, —OH, -(1-4C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and 
 n is 0, 1, 2, 3, 4, 5 or 6. 
 
     
     
       3. The method of  claim 1 , wherein:
 R 1  is H or -(1-6C alkyl); and 
 R 2  is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , -(1-6C alkyl)NHSO 2 (1-3C alkyl), -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl) 2 , -(1-6C alkyl)hetCyc 1 , -(1-6C alkyl)hetAr 1 , hetAr 2 , —O(1-6C alkyl), —O(3-6C cycloalkyl), or a 3, 4 or 5 membered cycloalkyl ring optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO 2 H and -(1-4C alkyl)OH, 
 or NR 1 R 2  forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from -(1-6C)alkyl, —OH, —CO 2 H and -(1-3C alkyl)CO 2 H. 
 
     
     
       4. The method of  claim 1 , wherein:
 R 1  is H or -(1-6C alkyl); 
 R 2  is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , -(1-6C alkyl)NHSO 2 (1-3C alkyl), -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl) 2 , -(1-6C alkyl)hetCyc 1 , -(1-6C alkyl)hetAr 1 , hetAr 2 , hetCyc 2 , —O(1-6C alkyl), —O(3-6C cycloalkyl), or a bridged 7-membered cycloalkyl ring, 
 or NR 1 R 2  forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from -(1-6C)alkyl, —OH, —CO 2 H and -(1-3C alkyl)CO 2 H. 
 
     
     
       5. The method of  claim 1 , wherein R 2  is H or -(1-6C)alkyl. 
     
     
       6. The method of  claim 5 , wherein R 2  is methyl, ethyl, isopropyl or tert-butyl. 
     
     
       7. The method of  claim 5 , wherein R 2  is H. 
     
     
       8. The method of  claim 1 , wherein R 2  is -(1-6C)hydroxyalkyl or -(2-6C)dihydroxyalkyl. 
     
     
       9. The method of  claim 8 , wherein R 2  is CH 2 CH 2 OH, CH 2 CH(OH)CH 2 OH or C(CH 3 )(CH 2 OH) 2 . 
     
     
       10. The method of  claim 1 , wherein R 2  is Cyc 1  or a bridged 7-membered cycloalkyl ring. 
     
     
       11. The method of  claim 10 , wherein R 2  is Cyc 1  optionally substituted with optionally substituted with one or two substituents independently selected from methyl, —OH, —CH 2 OH and —CO 2 H. 
     
     
       12. The method of  claim 11 , wherein R 2  is cyclopropyl. 
     
     
       13. The method of  claim 1 , wherein Cyc 1  is a 3, 4 or 5 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO 2 H, -(1-4C alkyl)OH, halogen and CF 3 . 
     
     
       14. The method of  claim 1 , wherein R 2  is cyclopropyl optionally substituted with one or more substituents independentlyselected from methyl, —CO 2 H, or —CH 2 OH. 
     
     
       15. The method of  claim 1 , wherein R 2  is —O(1-6C alkyl) or —O(3-6C cycloalkyl). 
     
     
       16. The method of  claim 15 , wherein R 2  is selected from —OMe, —OEt and cyclopropoxy. 
     
     
       17. The method of  claim 1 , wherein R 2  is selected from -(1-6C)fluoroalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , and -(1-6C alkyl)NHSO 2 (1-3C alkyl). 
     
     
       18. The method of  claim 17 , wherein R 2  is selected from —C(CH 3 ) 2 CH 2 F, —C(CH 3 ) 2 CH 2 OH, CH 2 C(CH 3 ) 2 OH, —CH 2 CN, —C(CH 3 ) 2 CN, —CH 2 CH 2 SO 2 NH 2 , —CH 2 CH 2 NHSO 2 CH 3  and —C(CH 3 ) 2 CH 2 NHSO 2 CH 3 . 
     
     
       19. The method of  claim 1 , wherein R 2  is selected from -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl) and -(1-6C alkyl)N(1-4C alkyl) 2 . 
     
     
       20. The method of  claim 1 , wherein R 2  is selected from -(1-6C alkyl)hetCyc 1  and -(1-6C alkyl)hetAr 1 . 
     
     
       21. The method of  claim 1 , wherein R 2  is selected from -(1-6C alkyl)hetAr 1  and hetAr 2 . 
     
     
       22. The method of  claim 1 , wherein R 1  is H. 
     
     
       23. The method of  claim 1 , wherein NR 1 R 2  forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from -(1-6C)alkyl, —OH, —CO 2 H and -(1-3C alkyl)CO 2 H. 
     
     
       24. The method of  claim 1 , wherein X is —CH 2 — or —CH 2 CH 2 —. 
     
     
       25. The method of  claim 1 , wherein X is —CH 2 O— or —CH 2 NR d —. 
     
     
       26. The method of  claim 1 , wherein Y is phenyl optionally substituted with one or more substituents independently selected from halogen, -(1-4C)alkoxy, CF 3 , CHF 2 , —O(1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3  and —O(1-4C alkyl)O(1-3C alkyl). 
     
     
       27. The method of  claim 26 , wherein Y is phenyl optionally substituted with one or more substituents independently selected from —F, —Cl, —OMe, —CF 3 , —CHF 2 , morpholinylethoxy, morpholinylethyl and —OCH 2 CH 2 OMe. 
     
     
       28. The method of  claim 27 , wherein Y is phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 2-chloro-5-fluorophenyl, 2-methoxyphenyl, 2methoxy-5-fluorophenyl, 2-trifluoromethyl-5-fluorophenyl, 2-difluoromethyl-5-fluorophenyl, 3-chloro-5-fluorophenyl, 3-fluoro-5-(2-morpholinylethoxyl)phenyl, 3-fluoro-5-(2-morpholinylethyl)phenyl, 5-fluoro-2-(2-morpholinylethyl)phenyl, 3-fluoro-5-methoxyethoxyphenyl or 5-fluoro-2-methoxyethoxyphenyl. 
     
     
       29. The method of  claim 1 , wherein Y is fluorophenyl optionally substituted with a substituent selected from —O(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl). 
     
     
       30. The method of  claim 29 , wherein Y is fluorophenyl substituted with a substituent selected from morpholinylethoxy, —OCH 2 CH 2 OMe,2,3-dihydroxypropoxy and 2,2-dimethyl-1,3-dioxolanyl. 
     
     
       31. The method of  claim 28 , wherein Y is 2,5-difluorophenyl. 
     
     
       32. The method of  claim 1 , wherein Y is a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein said ring is optionally substituted with one or more substituents independently selected from halogen, —O(1-4C alkyl) and (1-4C)alkyl. 
     
     
       33. The method of  claim 32 , wherein Y is pyridyl optionally substituted with one or more substituents independently selected from F, —OMe, ethyl and Me. 
     
     
       34. The method of  claim 33 , wherein Y is pyrid-2-yl, pyrid-3-yl, 5-fluoropyrid-3-yl, 2-methoxy-5-fluoropyridy-3-yl, 2-ethyl-5-fluoropyrid-3-yl or 2-methyl-5-fluoropyridy-3-yl. 
     
     
       35. The method of  claim 1 , wherein Y is a pyrid-2-on-3-yl ring optionally substituted with one or more substituents independently selected form halogen and (1-4C)alkyl. 
     
     
       36. The method of  claim 35 , wherein Y is 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl. 
     
     
       37. The method of  claim 1 , wherein:
 R 1  is H or -(1-6C alkyl); 
 R 2  is H, -(1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6C alkyl)SO 2 NH 2 , -(1-6C alkyl)NHSO 2 (1-3C alkyl), -(1-6C alkyl)NH 2 , -(1-6C alkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl) 2 , -(1-6C alkyl)hetCyc 1 , -(1-6C alkyl)hetAr 1 , hetAr 2 , hetCyc 2 , —O(1-6C alkyl), —O(3-6C cycloalkyl), or Cyc 1 ; 
 or NR 1 R 2  forms a 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from -(1-6C)alkyl, —OH, —CO 2 H and -(1-3C alkyl)CO 2 H; 
 Cyc 1  is a 3, 4 or 5 membered cycloalkyl ring which is optionally substituted with one or more substituents independently selected from -(1-4C alkyl), —OH, —OMe, —CO 2 H and -(1-4C alkyl)OH; 
 X is CH 2 ; and 
 Y is (i) fluorophenyl optionally substituted with a substituent selected from —O (1-4C alkyl)hetCyc 3 , -(1-4C alkyl)hetCyc 3 , —O(1-4C alkyl)O(1-3C alkyl) and —O(3-6C dihydroxyalkyl), (ii) pyridyl substituted with one or more substituents independently selected from F, methyl and ethyl, or (iii) 5-fluoropyridin-2(1H)-one optionally substituted with (1-4C)alkyl. 
 
     
     
       38. The method of  claim 1 , wherein R 4  is OH, F, methyl, or CH 2 OH. 
     
     
       39. The method of  claim 38 , wherein n is 0, 1 or 2. 
     
     
       40. The method of  claim 1 , wherein Y has the absolute configuration of Figure Ia: 
       
         
           
           
               
               
           
         
       
     
     
       41. The method of  claim 1 , wherein R 3  is H. 
     
     
       42. The method of  claim 1 , wherein n is 0-2 and R 4  is F or Me. 
     
     
       43. The method of  claim 42 , wherein n is 0.